Benzene-sulfonyl semicarbazides and process for preparing them

ABSTRACT

1. A BENZENE-SULFONYL SEMICARBAZIDE OF THE FORMULA 1-(R-CO-NH-Y-),4-(R1-NH-CO-NH-SO2-)BENZENE WHEREIN R REPRESENTS (A) PHENYL WHICH MAY CARRY ONE OR TWO SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL, LOWER ALKENYL, LOWER ALKOXY, LOWER ALKENOXY, LOWER ALKOXYALKOXY, ACETYL, HALOGEN, TRIFLUORO-METHYL, OR THE METHYLENE-DIOXY GROUP, (B) THIENYL WHICH MAY CARRY ONE OR TWO SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HALOGEN, LOWER ALKYL, LOWER ALKOXY LOWER ALKENYLOXY LOWER ALKOXYALKOXY, PHEN-LOWERALKOXY, OR POLYMETHYLENE CHAIN CONTAINING FROM 3 TO 4 CARBON ATOMS, LINKED AT ITS TWO ENDS TO THE THIENYL GROUP, Y REPRESENTS -CH2-CH2-, -CH2-CH-(CH3)OR -CH-(CH3)-CH2-, R1 REPRESENTS 4,7-ENDOALKYLENE-HEXAHYDRO-ISO-INDOLINE OR 4,7-ENDOALKYLENE-TETRAHYDRO-ISO-INDOLINE, HAVING 1 TO 2 CARBON ATOMS IN THE ENDOALKYLENE GROUP, IN THE CASE OF TETRAHYDROCOMPOUNDS THE DOUBLE LINKAGE DEING IN 5,6-POSITION; 4,7-ENDOCYCLOBUTYLENE-HEXAHYDROISO-INDOLINE; 4,7-ENDOCYCLOBUTYLENE-&amp;5-TETRAHYDRO-ISOINDOLINE; 4,7-ENDOCYCLOBUTYLENE-&amp;5 -TETRAHYDRO-SIOINDOLINE; OR 4,7-ENDOCYCLOPROPYLENE-HEXAHYDRO-ISOINDOLINE; AND SALTS THEREOF FORMED FROM PHARMACEUTICALLY ACCEPTABLE BASES.

United States Patent O Int. Cl. co7d 27/48 U.S. Cl. 260-326.1 4 ClaimsABSTRACT OF THE DISCLOSURE Benzene-sulfonyl semicarbazides havinghypoglycemic properties and corresponding to the general formula whereinR represents (a) phenyl which may be substituted once or twice bysubstituents of the group lower alkyl, alkenyl, alkoxy, alkenoxy,alkoxyalkoxy, acyl, halogen, or trifluoromethyl, or by themethylene-dioxy group,

(b) thienyl which may be substituted once or twice by substituents ofthe group halogen, lower alkyl, alkoxy, alkenyloxy, alkoxyalkoxy,phenalkoxy or aryl, or by a polymethylene chain linked at its two endsto the thienyl group, which chain contains from 3 to 4 carbon atoms;

R represents a hexahydro-iso-indoline, a tetrahydro-isoindoline, a4,7-endoalkylene-hexahydro-iso-indoline or a4,7-endoalkylene-tetrahydro-iso-indoline, having 1 to 2 carbon atoms inthe endoalkylene group, in the case of tetrahydro-compounds the doublelinkage being in 5,6-position; an iso.-indoline, an indoline, ahexahydroindoline, a tetraor decahydro-quinoline, a tetraordecahydro-iso-quinoline; 4,7-endocyclobutylene-hexahydro-iso-indoline;4,7-endocyclobutylene-A -tetrahydroiso-indoline;4,7-endocyclopropylene-A -tetrahydro-isoindoline; or4,7-endocyclopropenylene-hexahydro-isoindoline, and salts thereof.

This isa division of application Ser. No. 750,747, filed Aug. 7, 1968,now U.S. Pat. 3,705,151, issued Dec. '5, 1972. 4

The present invention provides benzene-sulfonyl' semicarbazides of theformula and definition set forth in the Abstract. The new semicarbazidesand their salts are valuable medicinal agents distinguished by a strongand par- .ticularly long-lasting blood-sugar lowering activity.

ice

sulfonamides, preferably in the form of their salts, with imino-carbamicacid esters, imino-thiocarbamic acid esters, or imino-ureas containingas imino radical the group 7 (b) Reaction of hydrazines of the formula R'NI -I or their salts with RCO-NHY-substituted benzenesulfonylisocyanates, benzenesulfonyl carbamic acid esters, benzenesulfonylthiolcarbamic acid esters, carbamic acid halides or ureas,

(c) Reaction of RCONH-Y-substituted benzenesulfo-chlorides with R-substituted ureas or preferably with their salts,

(d) Hydrolysis of benzenesulfonyl-isosemicarbazide ethers,isothiosemicarbazide ethers or benzenesulfonylimino-parabanic acids,

(e) Exchange of the sulfur atom for an oxygen atom, in benzenesulfonylthiosernicarbazides of the formula t Introduction of the radical RCO, ifdesired in by acylation.

The benzenesulfonyl semicarbazides obtained may then be converted, ifdesired, into their salts by treatment with alkaline agents or withphysiologically tolerable inorganic or organic acids.

As semicarbazides or imino-ureas for the syntheses mentioned under (a),there are suitable compounds of the formula R NH-CO-NH or acylatedcompounds of the formula R NHCONHacyl, wherein acyl represents analiphatic or aromatic acid radical, preferably of lower molecularweight, or diphenyl semicarbazides of the formula R NH-CON(C H whereinthe phenyl radicals may besubstituted or maybe linked to each otherdirectly or by means of a bridge member such as CH NH-, O or S, orN,N'-disubstituted carbohydrazides of the formula R -NH-CO-NH-REspecially suitable as benzenesulfonyl carbamic acid halides are thechlorides.

Furthermore,- corresponding benzenesulfonyl ureas which may beunsubstituted at the terminal nitrogen atom, or substituted once ortwice by alkyl or aryl groups, may be converted into the final productsby reacting these with hydrazines of the formula R -NH if desired, inthe form of their salts. Instead of the benzenesulfonyl ureassubstituted in this manner, there may be used the correspondingN-benzenesulfonyl-N'-acyl ureas, benzene-sulfonyl carbamoyl-imidazols,benzenesulfonyl-carbamoylpyrazols or benzene-sulfonylecarbamoyl-triazolsor bis- (benzenesulfonyD-ureas which carry at one of the nitrogen atomsanother substituent, for example methyl. Suchbis-(benzenesulfonyl)-ureas or N-benzene-sulfonyl-N'- acyl-ureas may betreated with hydrazines of the formula R NH and the salts obtained maybe heated to elevated temperatures, preferably to at least C.

The imino-carbamic acid esters or benzenesulfonyl carbamic acid estersmentioned, as well as the corresponding thioesters, contain in the estercomponent preferably an alkyl radical of low molecular weight or aphenyl radical.

The benzenesulfonyl isosemicarbazide ethers, -isothiosemicarbazideethers or -parabanic acids, used as starting materials, may be obtainedby reacting corresponding isosemicarbazide ethers, isothiosemicarbazideethers or parabanic acids with corresponding benzenesulfochlorides.Benzenesulfonyl isosemicarbazide ethers are also obtained, in the firstplace, by desulfurizing benzenesul- CHSO fonyl thiosemicarbazides inmethanol. They are subsequently converted into benzenesulfonylsemicarbazides by hydrolysis.

Depending on the nature of the member R--CO, in some cases, the one orthe other of the previously described methods may prove unsuitable forpreparing the individual compounds falling under the general formula, orat least will make it necessary for active groups to be protected. Suchrelatively rare cases can easily be recognized by the expert, and theiris no difficulty in successfully applying another one of the synthesesdescribed.

.As regards the reaction conditions, the process embodiments of thepresent invention may in general, vary within wide limits and may beadapted to each individual case. For example, the reactions can beeffected with the use of solvents, at room temperature or at an elevatedtemperature.

As starting substances there are used, as one reactant, compoundscontaining a benzene radical substituted by the group RCONHY. As radicalR may be mentioned, for example, the following groups:

CH3 C s CH Cl CH: 2 2

CH3 CH=CH1 Ha R may represent, for example:

The sulfonyl-semicarbazide derivatives obtainable according to thepresent invention, are valuable medicinal agents which are distinguishedby a strong action of lowering the blood sugar level. This applies, inparticular, to such compounds in which R represents a phenyl radicalcarrying an alkoxy group in 2-position. The blood sugar lowering actionof the products of the invention could be ascertained, for example, inrabbits, by administering the compounds in a dose of 10 mg./kg. and bydetermining the blood sugar value, over a prolonged period of time,according to the known method of Hagedorn-Jensen. The following tablecomprises the blood sugar lowering activities of some of the compoundsobtained according to the process of the present invention:

amido -ethyl) -benzenesulfunyl]- l,1-(2,5endoethylenehexamethylene)-semicarbazide.

In contradistinction thereto, the[N-(4-methylbenzenesulfonyl)-N'-n-butyl-urea] known as antidiabetic andused as medicinal agents shows no lowering of the blood sugar level whenadministered in a dose of 25 mgJkg. in a comparative test.

The toxicities of the products of the invention are very low, they arewithin the range of the above-mentioned N-(4methyl-benzenesulfonyl)N'-n-butyl-urea which is very well tolerable.

It'is preferable to process the products of the present invention intoorally administerable preparations which have blood sugar loweringaction and which can accordingly be used in the treatment of diabetesmellitus; these can be employed as such or in the form of their salts orin the presence of substances causing salt formation. For such saltformation there can be used, for example, alkaline agents such as alkalimetal hydroxides, alkaline earth metal hydroxides, alkali metalcarbonates, alkaline earth metal carbonates, alkali metal bicarbonatesand alkaline earth metal bicarbonates or physiologically toleratedacids. The pharmaceutical preparations are preferably in the form oftablets which contain, in addition to the compounds of the presentinvention, the usual adjuvants and carriers such as talc, starch,lactose, tragacanth, magnesium stearate and the like.

The following examples seive to illustrate the present invention, butthese are not intended to limit it thereto:

EXAMPLE 1 4 [4 (fl- 2 methoxy--chlorobenzamino -ethyl)- benzenesulfonyl]1,1 (2,5 endoethylene-hexamethylene) -semicarbazide 4.2 grams ofN-[4-(,6 2-meth0xy-5-chlorobenzamidoethyl)-benzenesulfonyl]-methyl-urethane (melting point 189191 C.) weresuspended in 75 milliliters of dioxane and 1.6 grams of1,1-(2,5-endoethylene-hexamethylene)- hydrazine were added thereto. Themixture was heated to 110 C. for 1 hour, after cooling it wasprecipitated by adding water and the 4-[4-(fi-2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonyl]1.1-(2,5-endoethylenehexamethylene)-semicarbazide obtained was purifiedby reprecipitating it with dilute ammonia/ glacial acetic acid andrecrystallization from methanol (melting point 173 175 C.).

In an analogous manner there were obtained:

from N [4-(fl- 3-trifluoromethyl-benzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 178- 180 C.) 4 [4 (/33-trifluoromethylbenzamido ethyD-benzenesulfonyl]-1.1 (2.5endoethylene-hexamethylene)-semicarbazide of the melting point 193- 195C. (from methanol);

from N [4 S- 3-chlorobenzamido -ethyl)-benzenesulfonyl]-methyl-utethane(melting point 173175 C.) 4 [4 (}3- 3 chlorobenzamido-ethyl)-benzenesulfonyl] 1.1 (2.5 endoethylene-hexamethylene)-semicarbazide of the melting point 198-200 C. (frommethanol/dimethylformamide) from N [4-( S-3-methoxythiophene-Z-carbonamido ethyl)-benzenesulfonyl]-methylurethane(melting point 226228 C.) 4 [4 (ti- 3 methoxythiophene-Z- carbonamido-ethyl)-benzenesulfonyl] 1.1 (2.5- endoethylenehexamethylene)semicarbazide, melting point 166-168 C. (from methanol);

from N [4 (B- 3.4 dichlorobenzamido -ethyl)benzenesulfonyl]methylurethane (melting point 198- 200 C.) 4 [4 (Ii-3.4-dichlorobenzamido -ethyl)- benzenesulfonyl] 1.1(2.5-endoethylene-hexamethylene)-semicarbazide, melting point 178-180 C.(from methanol/dimethylformamide) from N-[4-(B3.5-dimethylthiophene-Z-carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 170172 C.) 4 [4 (fi-3-5-dimethylthiophene-2- carbonamido -ethyl)-benzenesulfonyl] 1.1(2.5-endoethylene-hexamethylene)-semicarbazide, melting point 184-186"C. (from methanol);

from N- [4- (B- 2-methoxybenzamido -ethyl-benzenesulfonyl]-methylurethane (melting point 174-176 C.) 4 [4 (fl-2methoxybenzamido -ethyl)-benzenesulfonyl] 1.1 (2.5endoethylene-hexamethylene) 'semicarbazide, melting point ISO-152 C.(from methanol);

from N- [4- (B- 2-metl1oxy-5-methyl-benzamido -ethylbenzenesulfonyl]-methylurethane (melting point 175- 177 C.) 4 [4-(fi-2-methoxy-S-methylbenzamido ethyl)-benzenesulfonyl] 1.1 (2.5endoethylenehexamethylene) -semicarbazide, melting point 166168 C. (frommethanol);

from N- [4-( 8- 2-methoxy-5-bromo-benzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 197- 199 C.) 4 [4 (B-2-methoxy-5-bromobenzamido ethyl)-benzenesulfonyl] 1.1 (2.5endoethylenehexamethylene)semicarbazide, melting point 185-187" C. (frommethanol);

from N-[4-(B- 2-eth0xy 5 chlorobenzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 203- 205 C.) 4-[4-(B-2-ethoXy-5-chlorobenzamido ethyl) benzenesulfonyl] 1.1 (2.5endoethylenehexamethylene)-semicarbazide, melting point 196-198 C.(fi'om methano/dimethylformamide);

from N-[4 ([3 (3.5 dimethylbenzamido-ethyl)-benzenesulfonyl]-methylurethane (melting point223-225 C.) 4- [4(,8 3.5 dimethylbenzamido -ethyl)-ben+ zenesulfonyl]-1.1-(2.5endoethylene-hexamethylene)- semicarbazide, melting point 211-213 C.(from methanol/dimethylformamide) from N-[4-(I 2 ethoxy 5fiuorobenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point193- 195 C.) 4-[4- (ii- 2 ethoxy 5 fluorobenzamidoethyD-benzenesulfonyl] 1.1(2.5-endoethylene-hexamethylene)-semicarbazide, melting point 161163 C.(from methanol);

from N-[4-()3- -ethoxy-S-acetylbenzamido-ethyl)-benzenesulfonyl]-methylurethane (melting point 164166 C.) 4-[4-(;3- 2-ethoxy 5 acetylbenzamido -ethyl)- benzenesulfonyH-Ll (2.5endoethylene-hexamethylene)-semicarbazide, melting point 196-198 C.(from methanol);

from N- [4 (B 3 chlorobenzamido -ethyl)-benzenesulfonyl]-methylurethane(melting point 173-175 C.) N-[4 (,3 3 chlorobenzamido ethyl)benzenesulfonfonyl] -N' (decahydro-quinolino)-urea, melting point245-247 C. (decomposition) (from methanol/ dimethylformamide) fromN-[4-(,6 3 ethoxythiophene 2 carbonamidoethyl)-benzenesulfonyl]-methylurethane (melting point 163-165 C.) N- [4-B- 3-ethoxythiophene-2-carbonamido ethyl) benzenesulfonyl] Ndecahydroquinolino-urea, melting point 186187 C. (frommethanol/-dimethylformamide) from N- [4- (,8- 2-methoxybenzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 174-176 C.) N- [4-(;8- 2methoxybenzamido ethyl) benzenesulfonyl]-N'-decahydroquinolino-urea,melting point 205-206 C. (from methanol/dimethylformamide);

from N- [4- fi- Z-methoxy-S-chlorobenzanfido -etl1yl)-benzenesulfonyl]-methylurethane (melting point 19.3- 194 C.) N- [4-(5 2methoxy 5 chlorobenzamidoethyl)-benzenesulfonyl]N-decahydroquinolino-urea, melting point 218-219" C. (frommethanol/dimethylformamide) and N- [4 (13 2 methoxy 5 chlorobenzamido-ethyl) benzenesulfonyl] N-tetrahydroisoquinolino-urea, melting point148150 C. (from methanol);

from N-[4-(B- 2-methoxy-5-methylbenzamido -ethyl)-benzenesulfonyl]-methylnrethane (melting point 177 C.) N-[4-(,8-Z-methoxy-S-methylbenzamido ethyl)-benzenesulfonyl]-N'decahydroquinolino-urea, melting point ZOO-202 C. (frommethanol/dimethylformamide) and N-[4 (fl 2 methoxy 5 methylbenzamido-ethyl)-benzenesulfonyl] N tetrahydroisoquinolino-urea, melting point182-184 C. (from methanol/dimethylformamide) from N- [4-(B-3-methoxy 5chlorothiophene Z-carbonamido-ethyD-benzenesulfonyl]-methylurethane(melting point 186-188 C.) N-[4-([3 -3-methoxy-5-chlorothiophene 2carbonamido -ethyl)-benzenesulfonyl]- N-tetrahydr0isoquinolino-urea,melting point l77-179' C. (from methanol/dimethylformamide);

from N [4 (,8 2 methoxy-4-trifiuoromethylbenzamido ethyl)benzenesulfonyl] methylurethane (melting point 192 C.) N-[4-(fi-2-methoXy-4- trifluoromethylbenzamido ethyl)-benzenesulfonyl]-1.1-(2.5-endoethylene-hexamethylene) semicarbazide, melting point172-174 C. (from methanol);

from N- [4- (18- 2-methoXy-benzamido-ethyl)-benzenesulfonyl1-ethylurethane (melting point 144 C.) N-[4- (;3-2-methoxy-benzamido ethyl) benzenesulfonyl]-N-(3-azaspiro [5,5] undecyl3) urea (melting point 187-188 C.);

from N-[4-( 8- Z-methoxy-S-chloro-benzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 178- 179 C.) N-[4-(13-2-methoxy-5 chloro-benzamido ethyl) -benzenesu1fonyl] -N'- (3-azaspiro[5 ,5 -undecy1- 3)-urea (melting point 166169 C.) and N-[4-(p- 2-methoxy5 chloro-benzamido -ethyl)-benzenesulfonyl]-N'-(N-thiomorpholyl)-urea(melting point t 194196 0.); Y J from N-[4-(B-2-methoxy-S-methyl-benzamido -ethyl)- benzenesulfonyl]-ethylurethane(melting point 166- 170 C.) N-[4-(B- 2-methoXy-5-methyl-benzamidoethyl)-benzenesulfonyl]-N'-3 azaspir-[5,S]-undecyl- 3)-urea (meltingpoint 171-173 0.); from N-[4-(B- 2-methoxy-S-fluoro-benzamido -ethyl)-benzenesulfonyl]-ethylurethane (melting point 123 I C.) N-[4-(;3-2-methoxy-S-fluoro-benzamido -ethyl)- benzenesulfonyl]-N"-(3 azaspiro[5,5] undecyl-3)- V urea (melting'point 173 (2.); from N [4 (p benzamidoethyl) benzenesulfonyl1- methylurethane (melting point 186 C.) N-[4- (B-benzamido-ethyl)-benzenesulfonyl] N (3 azaspiro- [5,5]-unde cyl-3)-urea(melting point 186-187 C.); from N-[4-(B 3 chloro-benzamido-ethyl)-benzenesulfonyH-methylurethane (melting point 174-176 C.) N [4(,8 3 chloro benzamido ethyl) benzenesultonyl]-lf\l'-(3-azaspiro [5,5]undecyl-3)-urea (melting point 183-184 C.)..

EXAMPLE 2 N-[4-(18 2 methoxy chlorobenzamido -ethyl)-benzenesulfonyl]-N'-(4,7 methane heXahydro-iso-indolino-2 -urea 12.8grams of N-[4-(B-Z-methoxy-S-ch1orobenzamidoethyl)-benzenesulfonyl]-methyl urethane were dissolved in 150milliliters of dioxane. While stirring 4.6 grams ofN-amino-4,7-methano-hexahydro iso-indoline were added thereto and thewhole was heated to 100 C. for 1.5 hours while stirring was continued.After dioxane had been distilled oif in vacuo, the residue was dissolvedin dilute ammonia (1:25), filtered and acidified with dilute aceticacid. The N-[4-(B- 2 methoXy-5-chlorobenzamidoethyl)-benzenesulfonyl]-N'-(4,7 methano hexahydroiso-indolino-2)-ureathus obtained melted at 163-165 C. after recrystallizaton from dilutemethanol/dioxane.

In an analogous manner there were obtained from the correspondingsulfonyl-urethane (1 N- [4- (fl-benzarnido ethyl) -benzenesulfonyl] -N'-(4,

7-methano-hexahydro-isoindolino-2)-urea, melting point 190192 C. (fromdilute methanol/dioxane);

(2) N- [4-(,8- 4-chloro benzamido -ethyl)-benzenesul- 8hydro-isoindolino-2)-urea, melting point 173475? C.; (5)N-[4-(fl-benzamido ethyl) benzenesulfonyl]-N'+ (3,6endoethylene-hexamethylene-imino) urea, melting point 19ll93 C.' tWeclaim: I t 1. A benzene-sulfonyl semicarbazideof the formula wherein Rrepresents (a) phenyl which may carry one or two substituents selectedfrom the group consisting of lower alkyl, lower alkenyl, lower alkoxy,lower alkena oxy, lower alkoxyalkoxy, acetyl, halogen,trifiuoro-rnethyl, or the methylene-dioxy group,, 1 (b) thienyl whichmay carry one or two substitur ents selected from the group consistingof halogen, lower alkyl, lower alkoxy, lower alkenyloxy, loweralkoxyalkoxy, phen-loweralkoxy, or polymethylene chain containing from 3to 4 carbon atoms, linked at its two ends to the thienyl group,

'R represents 4,7-endoalkylene-hexahydro-iso-indoline or4,7-endoalkylene-tetrahydro-iso-indoline, having 1 to 2 carbon atoms inthe endo'al'kylene group. in the case of tetrahydrocompounds the doublelinkage being in 5,6-position;4,7-endocyclobutylene-hexahydroiso-indoline; 4,7-endocyclobutylene-A-tetrahydroisoindoline; 4,7-endoeyclopropylene-A tetrahydro-isoindoline;or 4,7-endocyclopropenylene-hexahydro-isoindoline; and salts thereofformed from pharmaceutically acceptable bases.

2. A benzene-sulfonyl semicarbazide as claimed in Claim 1, wherein Rrepresents phenyl substituted in 2- position by lower alkoxy.

3. A benzene-sulfonyl semicarbazide as claimed in Claim 1, wherein Rrepresents phenyl substituted in 2- position by lower alkoxy and in 4-or 5-positi0n by halogen, lower alkyl or lower alkoxy. 4. Abenzene-sulfonyl semic arbazide as claimed in Claim 1, wherein Rrepresents phenyl substituted in 2- position by methoxy and in5-position by halogen or methyl,

References Cited UNITED STATES PATENTS 3,503,962 3/1970 Beregietal260239.6 3,535,335 10/1970 Beregi et a1. 260-326.1

JOSEPH A. NARCAVAGE, Primary Examiner 7 U5. Cl. X.R.

260-243 B, 283 SA, 39 BF, 325.11 R; 424 274, 2ss, 244

1. A BENZENE-SULFONYL SEMICARBAZIDE OF THE FORMULA1-(R-CO-NH-Y-),4-(R1-NH-CO-NH-SO2-)BENZENE WHEREIN R REPRESENTS (A)PHENYL WHICH MAY CARRY ONE OR TWO SUBSTITUENTS SELECTED FROM THE GROUPCONSISTING OF LOWER ALKYL, LOWER ALKENYL, LOWER ALKOXY, LOWER ALKENOXY,LOWER ALKOXYALKOXY, ACETYL, HALOGEN, TRIFLUORO-METHYL, OR THEMETHYLENE-DIOXY GROUP, (B) THIENYL WHICH MAY CARRY ONE OR TWOSUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HALOGEN, LOWER ALKYL,LOWER ALKOXY LOWER ALKENYLOXY LOWER ALKOXYALKOXY, PHEN-LOWERALKOXY, ORPOLYMETHYLENE CHAIN CONTAINING FROM 3 TO 4 CARBON ATOMS, LINKED AT ITSTWO ENDS TO THE THIENYL GROUP, Y REPRESENTS -CH2-CH2-, -CH2-CH-(CH3)OR-CH-(CH3)-CH2-, R1 REPRESENTS 4,7-ENDOALKYLENE-HEXAHYDRO-ISO-INDOLINE OR4,7-ENDOALKYLENE-TETRAHYDRO-ISO-INDOLINE, HAVING 1 TO 2 CARBON ATOMS INTHE ENDOALKYLENE GROUP, IN THE CASE OF TETRAHYDROCOMPOUNDS THE DOUBLELINKAGE DEING IN 5,6-POSITION;4,7-ENDOCYCLOBUTYLENE-HEXAHYDROISO-INDOLINE;4,7-ENDOCYCLOBUTYLENE-&5-TETRAHYDRO-ISOINDOLINE;4,7-ENDOCYCLOBUTYLENE-&5 -TETRAHYDRO-SIOINDOLINE; OR4,7-ENDOCYCLOPROPYLENE-HEXAHYDRO-ISOINDOLINE; AND SALTS THEREOF FORMEDFROM PHARMACEUTICALLY ACCEPTABLE BASES.